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Mechanistic Deep Dive
HBV â HCC
- HBV integration into host genome
- Chronic inflammation
- Cirrhosis pathway
- HBx protein oncogenic
- Can occur without cirrhosis (HBV unique)
MASLD/MASH â HCC
- Metabolic stress
- Inflammation
- Fibrosis â cirrhosis â HCC
- Can occur without cirrhosis in some
- Rising globally
Atezolizumab + Bevacizumab Mechanism
- Atezolizumab: anti-PD-L1
- Bevacizumab: anti-VEGF (anti-angiogenic + immune microenvironment)
- Synergistic
- EGD before bev (variceal bleeding risk)
Durvalumab + Tremelimumab (STRIDE)
- Single priming dose tremelimumab (anti-CTLA-4)
- Followed by durvalumab (anti-PD-L1) monotherapy
- HIMALAYA trial
- No bevacizumab (alternative for varices/CV risk)
FGFR2 Fusion (iCCA)
- 10-15% intrahepatic CCA
- Pemigatinib, futibatinib, infigratinib
- Activating fusions
- Side effect: hyperphosphatemia, retinal detachment
IDH1 Mutation (iCCA)
- 15-20% intrahepatic CCA
- Ivosidenib FDA 2021
- 2-hydroxyglutarate accumulation
- ClarIDHy trial
Recent Trials & Updates
IMbrave150 (NEJM 2020)
- Atezo + bev vs sorafenib
- OS 19.2 vs 13.4 mo
- New first-line HCC standard
HIMALAYA (NEJM 2022)
- STRIDE (single tremelimumab priming + durvalumab)
- vs sorafenib
- OS 16.4 vs 13.8 mo
- Alternative first-line
TOPAZ-1 (NEJM 2022)
- Durva + cis/gem vs cis/gem
- OS 12.8 vs 11.5 mo
- New first-line CCA
KEYNOTE-966 (Lancet 2023)
- Pembro + cis/gem
- Similar to TOPAZ-1
- Confirmation
LEAP-002 (Failed)
- Pembrolizumab + lenvatinib
- Did not beat lenvatinib alone
CheckMate-9DW (2024)
- Nivolumab + ipilimumab vs lenvatinib/sorafenib
- Positive OS
- Potential new first-line
MERIT-12 / IMbrave050 (Adjuvant)
- Adjuvant atezo + bev for high-risk resected HCC
- Mixed results
High-Yield Specialist Points
AFP Limitations
- Not specific (can â in cirrhosis, hepatitis)
- Not sensitive (~ 50% miss)
- Use with US
- AFP > 400 with cirrhosis suggestive
- DCP (PIVKA-II) emerging
LI-RADS Categories
- LR-1 (definitely benign)
- LR-2 (probably benign)
- LR-3 (intermediate)
- LR-4 (probably HCC)
- LR-5 (definitely HCC) â no biopsy needed
- LR-M (probably/definitely malignant, not HCC)
- LR-TIV (tumor in vein)
Bridging/Downstaging
- TACE, TARE, ablation while awaiting transplant
- Downstaging to bring within Milan criteria
- UCSF criteria extended (†6.5 cm single or †3 †4.5 cm total †8 cm)
Combined Hepatocellular-Cholangiocarcinoma
- Mixed phenotype
- Worse prognosis
- Generally not transplant candidate
Fibrolamellar HCC
- Young adults (15-30)
- Non-cirrhotic liver
- No HBV/HCV association
- DNAJB1-PRKACA fusion
- Resection is mainstay
Cholangiocarcinoma Surgical Approach
- iCCA: hepatic resection
- pCCA (Klatskin): hepatectomy + bile duct excision + Roux-en-Y
- dCCA: Whipple
- Mayo protocol LT for hilar CCA
Lynch Syndrome and CCA
- Increased risk
- Family history important
Cholangioscopy
- SpyGlass
- Direct visualization
- Biopsy targeted
Photodynamic Therapy (PDT)
- Palliative for unresectable CCA
- Endoscopic
- Limited use
NET WHO Classification
- G1: Ki-67 < 3%
- G2: Ki-67 3-20%
- G3: Ki-67 > 20%
- NEC (neuroendocrine carcinoma) â poorly differentiated
- Different treatment approach (chemo)
MENA1 + NETs
- Pancreatic NETs (insulinoma, gastrinoma, others)
- Multiple endocrine neoplasia type 1
- RET/MEN2 = MTC
Pearls
- HCC surveillance: US ± AFP q6 mo
- LI-RADS LR-5 = HCC (no biopsy)
- BCLC integrates everything
- IMbrave150 = atezo + bev (first-line)
- HIMALAYA = STRIDE durva + treme
- Milan Criteria for transplant
- TOPAZ-1 = durva + cis/gem (CCA first-line)
- Pemigatinib (FGFR2), ivosidenib (IDH1) CCA
- Mayo Protocol for hilar CCA + LT
- GIST: imatinib (KIT/PDGFRA)